ABSTRACT/SUMMARY: PROJECT 3 An important mission of the NIH is to reduce the profound toll that chronic diseases take on individuals, families, and society. As life expectancy continues to rise, the spectre of Alzheimer's disease looms ever larger over the US and the rest of the world, yet there is no effective preventive or treatment for the disorder. To overcome this obstacle, it is essential to understand the fundamental biology of Alzheimer's disease, and important strides have been made in this regard in recent years. It is now evident, for example, that an early and obligatory event in the pathogenesis of Alzheimer's disease is the accumulation of an abnormally folded protein fragment called A. Surprisingly, however, recently developed methods for imaging these lesions in the living brain indicate that some people with large amounts of A pathology become demented, whereas others do not. In other words, not all aggregates of A appear to be equally toxic to brain cells. In this Project, we propose that the pathobiological characteristics of A result from variations in the multidimensional architecture of the misfolded protein. Specifically, we hypothesize that A can misfold and aggregate into different forms, or strains, and that these strains govern the toxicity of the molecules. To test this hypothesis, we propose to: 1) Investigate the molecular and structural features of aggregated A that define the strains; 2) Determine how these features affect the onset of Alzheimer's disease; 3) Identify other molecules within cells that influence the characteristics of A strains; and 4) Replicate A strains in transgenic mouse models of A pathology. By clarifying the nature and diversity of human A strains and their relationship to the disease phenotype, it is the objective of this project to identify new molecular therapeutic targets for Alzheimer's disease.